NOP agonists prevent the antidepressant-like effects of nortriptyline and fluoxetine but not R-ketamine

Rationale Nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of a Gi protein-coupled receptor named NOP. Both N/OFQ and NOP receptor are widely expressed in brain areas involved in the control of emotional processes. Clinical and preclinical studies support antidepressant effects due to the blockade of NOP receptor signaling. By contrast, NOP receptor activation did not evoke any change in behavioral despair tests. Objectives The present study aimed to investigate the effects of the co-administration of NOP agonists and classic antidepressant drugs in the forced swimming test (FST) and learned helplessness model (LH) in mice. Methods Male Swiss mice were co-administered with NOP agonists (N/OFQ and Ro 65-6570) and antidepressants (nortriptyline, fluoxetine, and R-ketamine) or SB-612111 (NOP antagonist) and the behavioral effects were assessed in the FST and LH tests. Results Fluoxetine, nortriptyline, R-ketamine and the NOP antagonist SB-612111 displayed antidepressant-like effects in the FST. The administration of the NOP agonists N/OFQ and Ro 65-6570 did not induce any behavioral change. However, co-administration of NOP agonists blocked the antidepressant effects of SB-612111, fluoxetine, and nortriptyline, but not R-ketaminein the FST. Similarly, in the LH, the systemic injection of SB-612111, nortriptyline, and R-ketamine reversed helplessness. The co-administration of Ro 65-6570 blocked the antidepressant-like effects of SB-612111 and nortriptyline, but not R-ketamine. Conclusions NOP receptor activation inhibits the acute antidepressant effects of nortriptyline and fluoxetine, but not R-ketamine. The present findings contribute to further understand the role played by the N/OFQ-NOP receptor system in regulating mood states.